The present invention concerns the synthesis production of taxol, taxol analogs and their intermediates. In particular, the present invention is directed to novel amine salt taxane derivatives.
Taxol is a naturally occurring taxane diterpenoid that has exhibited significant clinical activity as an antineoplastic agent with considerable potential for further development. The widespread treatment of candidates for taxol therapy is limited by the current scarcity of the drug. The low abundance of taxol in its natural source, the bark of the slow-growing Pacific yew, makes the long term prospects for the availability of taxol through isolation discouraging. Taxol has the general formula and a corresponding numbering system, as shown below: 
Among the solutions to the taxol supply problem addressable by organic chemists is the partial synthesis of the drug, or of clinically effective analogs, by the attachment to naturally derived substances like baccatin III of the A-ring side chain that protrudes from the C-13 position. The preparation of taxol and its analogs is known. For example, U.S. Pat. No. 4,924,011, issued May 8, 1990 to Denis et al discloses the process for preparing taxol by the condensation of a (2R,3S) side chain acid with a taxane derivative, followed by the removal of various groups protecting the hydroxyl groups. U.S. Pat. No. 4,924,012, issued May 8, 1990 to Colin et al discloses a process for preparing derivatives of baccatin III and of 10-deacetyl-baccatin III, by condensation of an acid with a derivative of baccatin III or of 10-deacetylbaccatin III, with the subsequent removal of protecting groups by hydrogen. Several syntheses of TAXOTERE(copyright) (Registered to Rhone-Poulenc Sante) and related compounds have been reported in the Journal of Organic Chemistry: 1986, 51, 46; 1990, 55, 1957; 1991, 56, 1681; 1991, 56, 6939; 1992, 57, 4320; 1992, 57, 6387; and 993, 58, 255; also, U.S. Pat. No. 5,015,744 issued May 14, 1991 to Holton describes such a synthesis.
The most straightforward implementation of partial synthesis of taxol requires convenient access to a chiral, non-racemic side chain and derivatives, an abundant natural source of baccatin III or closely related diterpenoid substances, and an effective means of joining the two. Of particular interest then is the condensation of Baccatin III and 10-deacetyl Baccatin III of the formulae: 
with the side chain: 
However, the esterification of these two units is difficult because of the hindered C-13 hydroxyl of baccatin III located within the concave region of the hemispherical taxane skeleton. For example, Greene and Gueritte-Voegelein reported only a 50% conversion after 100 hours in one partial synthesis of taxol. J. Am. Chem. Soc., 1988, 110, 5917. The Holten patent addresses one method of more efficient synthesis.
Still, a need exists for further efficient protocols for the attachment of the taxol A-ring side chain to the taxane skeleton (e.g., baccatin III) and for the synthesis of taxol, taxol analogs and their intermediates with variable A-ring side chain structures.
It is an object of this invention to provide compounds that are intermediates in the semi-synthesis of paclitaxel.
It is another object to provide new compounds each in the form of a suitable baccatin III or 10-deacetylbaccatin III backbone which has attached thereto at the C-13 position a suitable A-ring side chain C-3xe2x80x2 amine salt.
In its broad form, the present invention is directed to a chemical compound having a generalized formula: 
where R1 is +NH3Xxe2x88x92 where X is a deprotonated organic acid, such as deprotonated trifluoroacetic acid. R2 may be Acetyl or H, and P1 may be H or a benzyl-type protecting group, such as benzyloxymethyl. The present invention contemplates various particular compounds, such as ones in which X is deprotonated trifluoroacetic acid, R2 is Acetyl and P1 is H; in which X is deprotonated trifluoroacetic acid, R2 is Acetyl and P1 is benzyloxymethyl; in which X is deprotonated trifluoroacetic acid, R2 is H and P1 is H; and in which X is deprotonated trifluoroacetic acid, R2 is H and P1 is benzyloxymethyl. Other amine salt compounds according to the above formula having various deprotonated organic acids and benzyl-type protecting groups are also contemplated.